The long-term goal of this work is to achieve an understanding of the mechanism of HCl secretion by the stomach. The experimental approaches are directed toward membrane regulated events at several levels of organization, from intact tissue to component macromolecules. We will study the nature of secretagogue-receptor interaction in the regulation of HCl secretion using both isolated mammalian gastric mucosa and cell fractions derived therefrom. These studies will include the interrelationships between gastric secretagogues, their site of action and their influence on cyclic AMP metabolizing enzymes. We will use electrophysiological and isotopic flux methods to study the mechanistic interrelations between H ion and Cl minus transport across gastric mucosa. By a selective modification of membrane functional groups, specific ion transport sites will be localized and identified. The membrane modification approach will be evaluated in terms of pharmacological control of gastric secretion. Enzymes contributing to endergonic translocation mechanisms will be studied in membrane fractions from oxyntic cells. Of particular interest are the unique K ion-stimulated ATPase and K ion-activated phosphatase of gastric mucosa. Biochemical enzyme function will be studied, as well as the transport and accumulation function of these isolated membrane vesicle preparations. The oxyntic cell membrane glycoproteins will be isolated, characterized and studied with respect to their role as cytoprotective components against autodigestion. The techniques of electron microscopy, tracer identification and histochemical localization will be used to test the membrane transformation hypothesis of HCl secretion.